COVID-19-Related Administrative Supplement to NIA RF1 AG057409 under PA-18-591 and NOT-AG-20-022 PROJECT SUMMARY Epidemiological studies of pandemic COVID-19 suggest that aged populations, especially those with Alzheimer?s disease and related dementias (AD)/ADRD, are particularly vulnerable. We therefore propose an Administrative Supplement for work in line with the Division of Neuroscience at NIA, namely, ?studies aimed at discovery and development of novel drugs, as well as repurposing and repositioning existing drugs, for preventing and treating COVID-19, particularly drugs that are specific for COVID-19 related CNS targets and CNS mechanisms related to or driving the viral-mediated pathophysiology.? Specifically, we will test drugs developed in the parent RF1 award by screening them for anti-viral activity to fight the infection and treat potential CNS ramifications in AD/ADRD and aged populations. Intriguingly, aminoadamantane drugs (e.g., amantadine, rimantadine, and memantine) were first discovered as anti-viral agents because they can block the ion channel found in the envelope of viruses such as influenza, but also found in the SARS-CoV family. The PI, Dr. Lipton, subsequently found that these aminoadamantanes had activity in the CNS by blocking excessively-activated NMDAR-associated ion channels, and Lipton?s work eventually led to FDA approval of memantine for use in AD. Recently, the Lipton group designed and synthesized aminoadamantane nitrate drugs under the auspices of the parent RF1 Award to be used to inhibit excessively-activated NMDARs to a much higher degree than memantine by adding a nitro-based warhead to an aminoadamantane in order to S-nitrosylate (via covalent reaction of NO) and thus further inhibit receptor activity in a targeted fashion. As a seemingly amazing coincidence, it was recently reported that the SARS-CoV family of viruses are susceptible to NO, in part by inhibiting their replication cycle. However, the delivery of NO or a NO-related species to an already ill patient could have severe consequences, such as lowering the blood pressure dramatically. Hence, in this proposal we develop a novel targeted delivery of NO-related species directly to the SARS-CoV-2 virus by using the aminoadamantane moiety that binds to the envelope ion channel and has a nitro-based warhead that it then delivers directly to the virus. Another critical feature of the current proposal is that we use these same aminoadamantane nitrate compounds to protect the brain from injury potentially engendered by the virus via inhibition of excessive NMDAR activity. Importantly, up to 37% of patients hospitalized for severe COVID- 19 reportedly display neurological sequelae. Mechanistically in this regard, in the face of severe viral infections, including coronaviruses, excessive levels of glutamate are released (or not taken up) by astrocytes, leading to glutamate-related neurotoxicity (excitotoxicity). In our parent RF1 grant, we reported similar findings in AD, i.e., that A-stimulated astrocytes release glutamate onto neurons. Therefore, this Administrative Supplement will test the top ?hits? of aminoadamantane nitrates capable of inhibiting SARS-CoV-2 in additional screens for their ability to prevent viral-related damage to neurons in the brains of AD/ADRD and aged populations.